Nerve growth factor (NGF) plays a critical role in the development and growth of sensory neurons. Seminal studies suggest that NGF may also play an important role in the regulating the sensitivity of sensory neurons to noxious stimulation. NGF levels are elevated in inflammatory exudates and is a potent causative agent in the production of both thermal and mechanical hyperalgesia. The behavioral findings suggest that the heightened sensitivity that occurs with inflammation may, in part, result from the actions of NGF on sensory neurons. There have been very few studies exploring the sensitizing actions of NGF on isolated neurons and their associated signaling pathways. Recent work in my laboratory demonstrates that NGF can rapidly augment the excitability of small diameter, capsaicin-sensitive sensory neurons through enhancement of the TTX-resistant sodium current and suppression of a voltage-dependent potassium current(s). Thus, NGF may have a significant impact on the state of neuronal excitability. The notion that NGF may be an important paracrine-type messenger in mediating the excitability of sensory neurons on a rapid time scale, perhaps less than one minute, is a completely unexplored idea. The Specific Aims outlined in this proposal are: Aim 1 will determine the effects of NGF on the excitability as well as the modulation of a variety of membrane currents that are critical in setting the firing level of the neuron. These studies will establish whether this sensitization results from activation of Trk A and/or p75 NTR. Aim 2 will follow an identical course of study to determine whether the other neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) rapidly modulate the excitability and selected membrane currents. These studies will examine the role of Trk B, Trk C, and/or p75 receptors in modulating excitability. Aim 3 will establish whether glial cell-derived neurotrophic factor (GDNF) can rapidly modulate selected membrane currents in sensory neurons. GDNF plays a critical role in the growth and survival of a distinct population of non-peptidergic sensory neurons that lose their dependence on NGF. Aim 4 will explore the intracellular signaling pathways that mediate the rapid modulatory effects of NGF acting through Trk A and p75 NTRs, BDNF and NT-4 through Trk B, NT-3 through Trk C, and GDNF through the Ret kinase pathway. These studies will further our understanding of the cellular mechanisms and signaling pathways whereby neurotrophins acutely regulate the excitability of both nociceptive and non-nociceptive sensory neurons. A fundamental understanding of such events could lead to better designed compounds and therapies to facilitate the treatment of chronic inflammatory conditions. [unreadable] [unreadable]